The principal goal of this program project application is to carry out preclinical research on three new vaccine candidates against the backdrop of identifying correlates of protection in an existing protective vaccine model. These studies will provide the basis for a long-term program of the Institute of Human Virology (IHV) in which new vaccine candidates will be shepherded from conception through human trials. No human trials are proposed in this application by a process will be described whereby a candidate vaccine will be carried forward to such trials. This application represents our first step toward that goal. Accordingly, funds are requested for studies in which vaccine candidates will be refined or developed. This program consists of 4 projects. Project 1 tests the hypothesis that humoral responses to epitopes on a CD4-gp120 complex that determine co-receptor binding can protect against primary infection with HIV-1. Project 2 explores a new antigen delivery system that is based on attenuated bacterial toxins to elicit Class I MHC restricted T cell responses. Project 3 builds upon previous work from out group to develop and evaluate new Salmonella based delivery systems for HIV-1 and SIV antigens. Each of these 3 projects includes SHIV challenge studies to determine vaccine efficacy in an animal model. A major goal of these 3 projects is to identify at least one new vaccine candidate to carry forward to human trials by the end of the period of support. Project 4 seeks to define a correlate of protective immunity in a model of cross- protection induced by immunizing rhesus macaques with HIV-1 antigens and challenging them with HIV-2. This project will test the hypothesis that this cross protection is mediated by Virus Suppressive Factors (VSF) and/or anti-viral chemokines elaborated by T cells. A major goal of this project is to identify a correlate of protection that can be used to design new vaccines against human immunodeficiency viruses. Taken together, these 4 projects should provide significant new opportunities for the development of a safe and effective vaccine against HIV-1.